RGD Reference Report - Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor-beta-dependent and -independent Smad pathways: the role of Smad3. - Rat Genome Database

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Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor-beta-dependent and -independent Smad pathways: the role of Smad3.

Authors: Yang, F  Chung, AC  Huang, XR  Lan, HY 
Citation: Yang F, etal., Hypertension. 2009 Oct;54(4):877-84. Epub 2009 Aug 10.
RGD ID: 2314482
Pubmed: PMID:19667256   (View Abstract at PubMed)
DOI: DOI:10.1161/HYPERTENSIONAHA.109.136531   (Journal Full-text)

Connective tissue growth factor (CTGF) plays a critical role in angiotensin II (Ang II)-mediated hypertensive nephropathy. The present study investigated the mechanisms and specific roles of individual Smads in Ang II-induced CTGF and collagen I expression in tubular epithelial cells with deletion of transforming growth factor (TGF)-beta1, overexpression of Smad7, or knockdown of Smad2 or Smad3. We found that Ang II-induced tubular CTGF and collagen I mRNA and protein expressions were regulated positively by phosphorylated Smad2/3 but negatively by Smad7 because overexpression of Smad7-abolished Ang II-induced Smad2/3 phosphorylation and upregulation of CTGF and collagen I in vitro and in a rat model of remnant kidney disease. Additional studies revealed that, in addition to a late (24-hour) TGF-beta-dependent Smad2/3 activation, Ang II also induced a rapid activation of Smad2/3 at 15 minutes and expression of CTGF and collagen I in tubular epithelial cells lacking the TGF-beta gene, which was blocked by the addition of an Ang II type 1 receptor antagonist (losartan) and inhibitors to extracellular signal-regulated kinase 1/2 (PD98059) and p38 (SB203580) but not by inhibitors to Ang II type 2 receptor (PD123319) or c-Jun N-terminal kinase (SP600125), demonstrating a TGF-beta-independent, Ang II type 1 receptor-mediated extracellular signal-regulated kinase/p38 mitogen-activated protein kinase cross-talk pathway in Ang II-mediated CTGF and collagen I expression. Importantly, the ability of knockdown of Smad3, but not Smad2, to inhibit Ang II-induced CTGF and collagen I expression further revealed an essential role for Smad3 in Ang II-mediated renal fibrosis. In conclusion, Ang II induces tubular CTGF expression and renal fibrosis via the TGF-beta-dependent and -independent Smad3 signaling pathways, suggesting that targeting Smad3 may have therapeutic potential for hypertensive nephropathy.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to peptide hormone  IEP 2314482angiotensin IIRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccn2  (cellular communication network factor 2)


Additional Information